System  for treating brugada syndrome

ABSTRACT

Brugada syndrome and related forms of ion channelopathies, including ventricular asynchrony of contraction, originate in the region near the His bundle or para-Hisian regions of the heart. Manifestations of Brugada syndrome can be corrected by delivering endocardial electrical stimulation coincident to the activation wave front propagated from the atrioventricular (AV) nodeearly enough to compensate for the conduction problems that start in those region. The stimulation can include waveforms of the same polarity delivered to a site within the region near the His bundle or para-Hisian regions of the heart associated with a low cardiac electrical asynchrony level or can include at least two single-phased superimposed waveforms of opposite polarity delivered through a pair of pacing electrodes relative to a reference electrode, which can be delivered to any site within the region near the His bundle or para-Hisian regions of the heart.

CROSS-REFERENCE TO RELATED APPLICATION

This non-provisional patent application is a continuation-in-part ofU.S. patent application Ser. No. 15/474,950, filed Mar. 30, 2017,pending, the disclosures of which are incorporated by reference.

FIELD

This application relates in general to treatment of cardiac rhythmdisorders and, in particular, to a system for treating Brugada syndrome.

BACKGROUND

Brugada syndrome is a distinct form of genetically-determined idiopathiccardiac arrhythmia syndrome that can lead to syncope, cardiac arrest andsudden cardiac death (SCD). The syndrome is a genetic form of cardiacrhythm disorder caused by an inherited ion channelopathy. Brugadasyndrome has been observed in the electrocardiograms of otherwisehealthy young individuals without evidence of structural heart diseasewho are of Southeast Asian descent. Men are eight to ten times morelikely to suffer Brugada syndrome. The syndrome has anautosomal-dominant pattern of transmission in about half of the familialcases observed and primarily affects Southeast Asian men, especiallyThai and Laotian, in the 30-50 year age range, with a median age of 41years.

The prognosis in Brugada syndrome is poor. Although the exact incidenceof SCD due to Brugada syndrome is unknown, the magnitude of the problemhas been estimated to range from 180,000 to 450,000 deaths annually inthe United States alone. Further, about 2.5% of all cardiac arrest casesin which the patient showed no clinically identifiable cardiacabnormalities have been attributed to Brugada syndrome. The syndromealso accounts for 4% to 12% of all SCDs in genetically pre-disposedindividuals, and a 40% mortality rate has been observed in symptomaticpatients at two to three years follow up, with a 2% to 4% mortality ratein asymptomatic patients. During electrophysiologic studies (EPS),asymptomatic patients with induced ventricular tachycardia (VT) orventricular fibrillation (VF) exhibited four times more SCD thannon-inducible patients.

The cause of death in Brugada syndrome is due to VF, yet the precisemechanism underlying the electrocardiographic changes observed insymptomatic patients having Brugada syndrome is unknown. Pathologically,in 20% of observed cases, the syndrome has been associated withmutations in SCN5A gene expression, located in chromosome 3, whichencodes for sodium ion channel transport to cell membranes of cardiacmyocytes. Loss-of-function mutations in this gene have been theorized tolead to a failure of the action potential dome to develop, that in turncauses persistent ST segment elevation. The clinical events observedcoincident to the electrocardiographic markers of Brugada syndrome, fromsyncope to VT to VF to SCD, are triggered by polymorphic ventriculararrhythmias, whose mechanism could be a Phase 2 reentry in the areaaround the right ventricular outflow tract.

Conventional approaches to treating Brugada syndrome focus on preventingor ameliorating VT and VF. For instance, implantable cardiac rhythmmanagement devices, particularly automatic implantablecardioverter-defibrillator (ICDs), and, to a lesser extent,transiently-introduced electrophysiology catheters, apply a therapybased on the reversion of already-established polymorphic arrhythmias,such as described in Lee et al., “Prevention of Ventricular Fibrillationby Pacing in a Man with Brugada Syndrome,” J. Cardiovasc.Electrophysiol., Vol. 11, pp. 935-937 (August 2000), the disclosure ofwhich is incorporated by reference. Similarly, Quinidine-basedpharmaceutical therapies have also been used to effectively prevent VFinduction and suppress spontaneous arrhythmias. Finally, surgicalinterventions through ablation at the right ventricular outflow tractlevel have been explored. Notwithstanding, these approaches constituteaggressive interventions and are impracticable to use on the largepopulation that is theorized to have the Brugada syndrome, as only asmall percentage will develop VT or VF, or experience cardiac arrest orSCD.

Therefore, a need remains for an approach to proactively treating theconduction and activation problems underlying the Brugada syndrome,rather than focusing on only avoiding or alleviating the deleterioussequalae of the syndrome.

A further need exists for an approach that can utilize commerciallyavailable cardiac arrhythmia devices for treating the conduction andactivation problems underlying the Brugada syndrome.

SUMMARY

Brugada syndrome and related forms of ion channelopathies, includingventricular asynchrony of contraction, originate around the rightventricular outflow tract, the region near the His bundle or para-Hisianregion of the heart. Manifestations of Brugada syndrome can be correctedby delivering endocardial electrical stimulation coincident to theactivation wave front propagated from the atrioventricular (AV) node.The stimulation can include waveforms of the same polarity or caninclude at least two single-phased superimposed waveforms of oppositepolarity delivered through a pair of pacing electrodes relative to areference electrode. Whereas delivering stimulation that includes atleast two single-phased superimposed waveforms of opposite polarity iseffective at correcting manifestations of the Brugada syndrome whendelivered to any site within the region near the His bundle orpara-Hisian region, the Brugada syndrome manifestations can also becorrected when stimulation that only includes waveforms of the samepolarity is delivered to a site within the region near the His bundle orpara-Hisian region that is selected because of a low level of cardiacelectrical asynchrony associated with delivering pacing to that site.The approach involving only waveforms of the same polarity may beimplemented using commercially available pacing electrodes, and thus maybe used to treat the Brugada syndrome even when all of the componentsnecessary to deliver the at least two single-phased superimposedwaveforms of opposite polarity are not readily available. In oneembodiment, a system for treating Brugada syndrome is provided. Thesystem includes a cardiac pacing device including a pulse generator andat least one pacing electrode that is electrically coupled to the pulsegenerator via an endocardial lead, the at least one pacing electrodeconfigured to be positioned in one of a plurality of potential pacingsites that is selected based on a level of cardiac electrical asynchronyassociated with that potential pacing site, the selected potentialpacing site located in one of a region near the His bundle and apara-Hisian region of a patient's heart, the pulse generator configuredto deliver through the at least one pacing electrode therapeuticelectrical stimulation substantially coincidentally to propagation of anactivation wave front proceeding from the atrioventricular node of thepatient's heart when the at least one pacing electrode is positioned atthe selected potential pacing site.

In a further embodiment, a system for catheter-based treatment Brugadasyndrome is provided. The system includes an electrophysiology catheterconfigured to be transiently introduced into a patient's heart. Thesystem further includes a pulse generator and at least one pacingelectrode that is electrically coupled to the pulse generator via thedefibrillation lead, the at least one pacing electrode configured to bepositioned in one of a plurality of potential pacing sites that isselected based on a level of cardiac electrical asynchrony associatedwith that potential pacing site, the selected potential pacing sitelocated in one of a region near the His bundle and a para-Hisian regionof a patient's heart, the pulse generator configured to deliver throughthe at least one pacing electrode therapeutic electrical stimulationsubstantially coincidentally to propagation of an activation wave frontproceeding from the atrioventricular node of the patient's heart whenthe at least one pacing electrode is positioned at the selectedpotential pacing site.

In a still further embodiment, a system for treating Brugada syndromeusing cardiac electrical asynchrony data is provided. The systemincludes a processing device configured to determine, for a plurality ofpotential pacing sites in at least one of a region near the His bundleand a para-Hisian region of a patient's heart, a level of cardiacelectrical asynchrony associated with an application of therapeuticelectrical stimulation to each of the plurality pacing sites; and apulse generator electrically coupled to one of an endocardial lead and aphysiological catheter and configured to deliver electrical therapeuticstimulation under programmed parametric control through an at least onepacing electrode, the at least one pacing electrode comprised on one ofthe endocardial lead and the physiological catheter, substantiallycoincidentally to propagation of an activation wave front proceedingfrom the atrioventricular node of the patient's heart when the at leastone pacing electrode is positioned at the potential pacing siteassociated with the lowest one of the levels of the cardiac electricalasynchrony.

Still other embodiments will become readily apparent to those skilled inthe art from the following detailed description, wherein are describedembodiments by way of illustrating the best mode contemplated. As willbe realized, other and different embodiments are possible and theembodiments' several details are capable of modifications in variousobvious respects, all without departing from their spirit and the scope.Accordingly, the drawings and detailed description are to be regarded asillustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing placement of an implantablecardiac rhythm management device in a male patient for treating Brugadasyndrome, in accordance with one embodiment.

FIGS. 2 and 3 are graphs showing, by way of example, 12-leadelectrocardiograms for patients exhibiting Brugada syndrome.

FIG. 4 is a flow diagram showing a method for treating Brugada syndromethrough triggered pacing in accordance with one embodiment.

FIG. 5 is a flow diagram showing a method for treating Brugada syndromethrough optimized atrioventricular nodal pacing in accordance with afurther embodiment.

FIG. 6 is a flow diagram showing a method 100 for selecting an algorithmfor detecting Brugada syndrome for use in conjunction with the methodsof FIGS. 4 and 5.

FIGS. 7A-B, 8A-B and 9A-B are graphs respectively showing, by way ofexample, 12-lead electrocardiograms for patients exhibiting Brugadasyndrome following treatment through the methods of FIGS. 4 and 5 thatinvolved application of at least two single-phased superimposedwaveforms of opposite polarity with respect to the indifferentelectrode.

FIGS. 10A-10C are graphs respectively showing, by way of example,12-lead electrocardiograms for a patient exhibiting Brugada syndromebefore, during, and after application of therapeutic stimulationinvolving only waveforms of the same polarity by the CRM device.

FIGS. 11A-11C, are graphs respectively showing, by way of example,12-lead electrocardiograms for a second patient exhibiting Brugadasyndrome before, during, and after application of therapeuticstimulation involving only waveforms of the same polarity by the CRMdevice.

FIGS. 12A-12C, are graphs respectively showing, by way of example,12-lead electrocardiograms a third patient exhibiting Brugada syndromebefore, during, and after application of therapeutic stimulation by theCRM device.

FIG. 13 is a flow diagram showing a method 100 for sensing QRS width foruse in conjunction with the methods of FIGS. 4 and 5.

FIG. 14 is a functional block diagram showing a computer-implementedsystem for treating Brugada syndrome, in accordance with a furtherembodiment.

FIG. 15 is a flow diagram showing a routine 150 for selecting a site fordelivering therapeutic stimulation by the pacing electrode in the regionnear the His bundle or the para-Hisian region for use in the methods ofFIGS. 4 and 5 in accordance with one embodiment.

FIG. 16 shows surface ECG curves representing both left ventricle andright ventricle of a patient superimposed in their final portion, withthe left ventricle and the right ventricle exhibiting a high degree ofsynchrony.

FIG. 17 shows surface ECG curves representing both left ventricle andright ventricle of the same patient whose 12-lead ECG is shown withreference to FIG. 10A and which are contemporaneous to the 12-lead ECGshown in FIG. 10A.

FIG. 18 shows surface ECG curves representing both left ventricle andright ventricle of the same patient whose 12-lead ECG is shown withreference to FIG. 10B and which are contemporaneous to the 12-lead ECGshown in FIG. 10B.

FIG. 19 is a front anatomical diagram showing placement of animplantable CRM device in a male patient for treating Brugada syndrome,in accordance with a further embodiment.

FIG. 20 is a front anatomical diagram showing placement of atransiently-introduced catheter in a male patient for treating Brugadasyndrome, in accordance with one embodiment.

FIG. 21 is a close-up view of FIG. 19 showing the endocardial leadwithin the heart in accordance with one embodiment.

DETAILED DESCRIPTION

Implantable cardiac rhythm management (CRM) devices include pacemakers,implantable cardioverter-defibrillators (ICDs), and cardiacresynchronization therapy (CRT) devices. CRM devices and, to a lesserextent, transiently-introduced electrophysiology catheters, such as usedto induce ventricular arrhythmias during electrophysiologic studies(EPS), currently provide the only effective means for treating thesequalae VT and VF triggered by the syndrome and thereby help to preventSCD. However, these devices focus on preventing or ameliorating VT andVF, rather than directly addressing the elimination of theelectrocardiographic pattern typical of Brugada syndrome and relatedforms of channelopathies and cardiac asynchrony disorders.

Conventional arrhythmia management using CRM devices is episode-focused.Changes in heart rhythm are monitored by a CRM device as arrhythmicepisodes potentially requiring therapy to convert, mitigate, orinterrupt the dysrhythmia. Pacemakers, for instance, manage bradycardia,which is an abnormally slow or irregular heartbeat, by delivering pacingstimuli to restore normal sinus rhythm through electrodes provided onendocardial pacing leads. Implantable cardioverter defibrillators (ICDs)treat tachycardia, which are abnormally fast and life threatening heartrhythms, through high energy cardioversion, defibrillation shocks, oranti-tachycardia pacing.

Brugada syndrome, as well as other forms of conduction problems thatstart in the His and para-Hisian regions, such as ventricular asynchronyof contraction, can be corrected by actively stimulating those regionsof the heart as the activation wave front coming from theatrioventricular (AV) node enters using an implantable CRM device. FIG.1 is a front anatomical diagram showing placement of an implantable CRMdevice 19 in a male patient 10 for treating Brugada syndrome, inaccordance with one embodiment. Depending upon type, CRM devices canprovide therapeutic electrical stimuli for up to three chambers of theheart. Single-chamber CRM devices rely on one endocardial lead attachedto either the right atrium or right ventricle, while dual-chamber CRMdevices utilize a pair of endocardial leads attached to the right atriumand right ventricle. Triple-chamber CRM devices use endocardial leads inthe right atrium and right ventricle and coronary venous leads in theleft ventricle.

The implantable CRM device 19 is preferably at least a dual-chamber CRMdevice that is surgically implanted subcutaneously in the patient'spectoral region or other suitable location in situ. A pair ofdual-chamber endocardial leads 21, 22 are guided through the leftsubclavian vein (not shown) and superior vena cava 18 into the rightatrium 12 and right ventricle 13 of the heart 11 for providing cardiacphysiological monitoring within and for delivering electrical therapy tothe patient's heart 11. The implantable CRM device can further includean additional endocardial lead 201 that is similarly guided into theheart into the right atrium 12 for sensing atrial activity. For the sakeof clarity, the endocardial leads 201, 21, 22 are shown leading directlyinto the heart 11, although different placement and orientation may beused during actual implantation. Other forms of CRM may requireplacement of endocardial leads in the left atrium 14 or left ventricle15 of the heart 11. For the sake of completeness, two endocardial leads21, 22 are shown, although only the endocardial lead 21 and its pacingelectrodes 23 that are distally located in the region near the Hisbundle 16 or para-Hisian region 17 are directly addressed in thedelivery of pacing therapy for treating Brugada syndrome, as can be seenwith reference to FIG. 19, which is a front anatomical diagram showingplacement of an implantable CRM device 19 in a male patient 10 fortreating Brugada syndrome, in accordance with a further embodiment.

The endocardial leads 21, 22, 201 are screw-in leads FIG. 21 is aclose-up view of FIG. 19 showing the endocardial lead 21 within theheart 11 in accordance with one embodiment. As can be seen withreference to FIG. 21, the screw 202 portion of the lead 21 secures thelead within the cardiac tissue being stimulated. While the screws 202are not shown with reference to FIGS. 1 and 19, the screws 202 are alsoparts of the endocardial leads 21 shown with reference to these FIGUREs.Likewise, the screw 202 is a part of a catheter 190 shown with referenceto FIG. 20.

In the general sense, electrical stimuli can be delivered through pacingelectrodes 23, 25 respectively on the distal ends of each of theendocardial leads 21, 22, although only the pacing electrodes 23 thatare distally located in the region near the His bundle 16 or thepara-Hisian region 17 are of interest herein. By way of example, thepacing electrodes 23, 25 are bipolar electrodes, but the pacingelectrodes could also be unipolar or tripolar. In a further embodiment,the endocardial leads 21, 22 can also respectively include sensingelectrodes 24, 26 located near their distal ends for monitoringphysiology indicative of a presence of Brugada syndrome. In a stillfurther embodiment, the pacing electrodes 23, 25 could be alternativelyre-purposed to sense physiology between deliveries of electricalstimuli.

The implantable CRM device 19 also encloses operational circuitry withina hermetically-sealed housing 28, which generally includes controlcircuitry 27; inductive transducer 28; oscillator 29; wirelesstransceiver 30; memory 31; and power source 32, which provides a finitepower supply for the operational circuitry. The control circuitry 27implements the implantable CRM device's functionality and controls pulsegenerator output circuitry 33 for delivering electrical stimulationtherapy through the pacing electrodes 23, 25 to the heart 11, andsensing amplifiers 34 for monitoring cardiac physiology in the heart 11through the sensing electrodes 24, 26. The transducer 28 providesinductive signal conversion to enable remote parametric programming ofthe implantable CRM device 19 and stored physiologic data offload fromthe memory 31 through an external programmer or similarinductively-coupled device, as further described infra with reference toFIG. 11. The oscillator 29 regulates internal CRM device operation bycontrolling timing. The wireless transceiver 30 enables wirelesscommunications with an external computer or similarwirelessly-interfaced device, as also further described infra withreference to FIG. 11. Finally, the memory 31 stores monitored cardiacphysiology, such as the patient's monitored physiometry; environmentaldata, for instance, ambient temperature or time of day; and parametricinformation, including programming, status, and device operationalcharacteristics for the implantable CRM device 19 proper. The parametricinformation can include pacing parameters, including electrical stimuliwaveform, voltage, amplitude, phase, pulse width, rate, inter-pulsedelay, pacing duration, inter-pacing delay, and so forth. Still otherkinds of parametric information and pacing parameters are possible.

Brugada syndrome is a genetic disease characterized by abnormalelectrocardiogram findings and an increased risk of cardiac arrest andSCD, such as described in Braunwald, “Heart Disease—A Textbook ofCardiovascular Medicine,” p. 904 (8^(th) ed. 2008), the disclosure ofwhich is incorporated by reference. FIGS. 2 and 3 are graphsrespectively showing, by way of example, 12-lead electrocardiograms 40,50 for patients exhibiting Brugada syndrome. The syndrome is primarilycharacterized by an electrocardiogram 40, 50, or similartemporally-captured cardiac cycle physiology, that exhibits an STsegment elevation in the anterior precordial (V1, V2, V3) leads with QRScomplexes exhibiting an image of right bundle branch block in the rightprecordial leads and an elevation at the J point, which are respectivelyindicated by boxes 41, 51. In general, the electrocardiogram pattern canbe of three types, Type 1 with covered-type ST segment, Type 2 withsaddleback ST segment and Type 3 with ST segment elevated less than 1mm.

Clinically, a QRS duration in lead V2 longer than 90 msec combined withan inferolateral J wave or horizontal ST segment morphology followingthe J wave can serve as predictors of cardiac events for purposes oftreating Brugada syndrome. Referring back to FIG. 1, Brugada syndrome,as well as other forms of related conduction problems, can be correctedby actively stimulating the region near the His bundle 16 or thepara-Hisian region 17. Two forms of pacing are used. In the first form,electrical stimulation is triggered by the direct early detection of thearrival of an activation wave front from the AV node 36 to the Hisbundle 16 or para-Hisian regions 17 of the patient's heart 11, asfurther described infra with reference to FIG. 4. In the second form,electrical stimulation is triggered by an atrial activity, which can besensed in lieu of or in addition to His or para-Hisian events, asfurther described infra with reference to FIG. 5.

Empirically, the electrocardiographic pattern characteristic of Brugadasyndrome can be eliminated by using an ample combination of pacing sitesand electrical stimulation amplitudes around the region near the Hisbundle 16 or in the para-Hisian region 17, on either the right atrialand right ventricular sides of the tricuspid valve 35, or in somecombination thereof. A virtual pacing electrode, when applied to theright region of the septum, allows the Brugada syndromeelectrocardiographic pattern to be normalized and the conduction andactivation abnormalities that created the pattern to be corrected. Inone embodiment, the endocardial lead 21 is guided through the tricuspidvalve 35 and the pacing electrodes 23 are placed in the para-Hisianregion 17 towards the right ventricular outflow tract, such as describedin Nakagawa et al., “Para-Hisian pacing: Useful clinical technique todifferentiate retrograde conduction between accessory atrioventricularpathways and atrioventricular nodal pathways,” Heart Rhythm, Vol. 2(6),pp. 667-72 (June 2005), the disclosure of which is incorporated byreference. In a further embodiment, the pacing electrodes 23 are placedin the region near the His bundle 16 at a point near the AV septum,superior to the tricuspid valve 35, such as described in Deshmukh etal., “Permanent, Direct His-Bundle Pacing,” Circulation, Vol. 101, pp.869-977 (2000), the disclosure of which is incorporated by reference. Asfurther described below, there are multiple sites within both thepara-Hisian region 17 and the region near the His bundle 16 where thepacing electrodes 23, 25 can be positioned, and, in one embodiment, theoptimum site for delivery of the pacing can be selected by evaluatingcardiac asynchrony associated with delivering pacing to that site.

Empirically, these pacing locations have been found to deliver optimumstimulation therapy when using an implanted endocardial pacing lead 21or, in a further embodiment, when using an transiently-introducedelectrophysiology catheter, shown below with reference to FIG. 20. Inone embodiment, the pulse generator 33 delivers a ventricular pacingoutput of at least two single-phase superimposed waveforms of oppositepolarity with respect to an indifferent (reference) electrode (notshown). The indifferent electrode could be located as a third electrodein a tripolar lead, an exposed metallic surface on the implantable CRMdevice's housing 28, an electrode connected to the implantable CRMdevice 19 proper, or other type of reference voltage lead. A pulsegenerator and single-phase superimposed waveforms of opposite polarityas used to bypass a conduction defect causing an asynchronouscontraction of the heart, such as described in U.S. Patent App. Pub. No.2012/0053651, the disclosure of which is incorporated by reference,could be used as the implantable CRM device 19.

The delivery of the two single-phased superimposed waveforms of oppositepolarity with respect to the indifferent electrode may require aredesign of existing hardware platforms in commercially availableimplantable devices. As such redesigns may require investment ofadditional resources, the delivery of the two-single phased superimposedwaveforms through the electrodes 23, 25 may not always be practicable.

Accordingly, in a further embodiment, the CRM device 19 can achievenormalization of the Brugada syndrome electrocardiographic pattern andthe correction of the conduction and activation abnormalities throughdelivery of only conventional pacing waveforms: pulse waveforms of thesame polarity with respect to the indifferent electrode to a site withinthe region near the His bundle 16 or the para-Hisian region 17. Asfurther described below, the site selection for the stimulation isassociated with a low level of cardiac electrical asynchrony. Theelectrical therapeutic stimulation can be delivered through a singlepacing electrode 23, 25 coupled to the lead 21, though in a furtherembodiment, multiple pacing electrodes 23, 25 can be used to deliver thestimulation. While, as described above, the CRM device 19 can include apacemaker, an ICD, and cardiac resynchronization therapy (CRT) devices,including an ICD into the CRM device 19 provides additional protectionfor the patient against SCD. Accordingly, if the CRM device 19 includesan ICD, the endocardial lead 21 coupled to the pacing electrode 23, 25can be a defibrillation lead, though other kinds of leads 21 arepossible. The delivery of the therapeutic electrical stimulation ofpulses of the same polarity can be performed using commerciallyavailable electrodes, making the CRM device 19 more widely available fortreatment of the Brugada syndrome.

As further described below, the normalization of the Brugada syndromeelectrocardiographic pattern can also be achieved using atransiently-introduced electrophysiology catheter, in conjunction withan external pulse generator, such as used to induce ventriculararrhythmias during EPS. FIG. 20 is a front anatomical diagram showingplacement of a transiently-introduced catheter 19 in a male patient 10for treating Brugada syndrome, in accordance with one embodiment. Thecatheter 190 is connected to the external pulse generator 191 and candeliver stimulation to the para-Hisian 17 region or the His bundle 16via at least one pacing electrode 193 (which can be a bipolar electrode,though in a further embodiment, the electrode can be a tripolar or aunipolar electrode). The catheter 190 can further include at least onesensing electrode 194 located near the catheter's distal end formonitoring physiology indicative of a presence of Brugada syndrome,which can be processed by processing circuitry (not shown) coupled tothe external pulse generator 191. In a further embodiment, a furthercatheter (not shown) can be introduced into the right atrium 12 forsensing atrial activity, with the sensed activity being processed by theprocessing circuitry coupled to the external pulse generator 191. Thecatheter 190 can deliver conventional pacing or pacing that involvesdelivery of at least two single-phase superimposed waveforms of oppositepolarity with respect to an indifferent (reference) electrode.

Multiple potential sites where the pacing electrode 23, 25, 193 withinthe region near the His bundle 16 or the para-Hisian region can bepositioned are possible. While electrical therapeutic stimulation thatemploys at least two single-phased superimposed waveforms of oppositepolarity with respect to the indifferent electrode is effective whenapplied to any of the potential pacing sites within the region near theHis bundle 16 or the para-Hisian region 17, treatment of the Brugadasyndrome using pulse waveforms of the same polarity requires carefulselection of the pacing site due to potential cardiac asynchrony.Cardiac pacing can contribute to appearance of intraventricular andinterventricular electrical asynchrony in a patient, which in turn caninterfere with effects of anti-Brugada pacing.

Applying pacing utilizing pulse waveforms of the same polarity to apacing site that is associated with a low level of intraventricularelectrical asynchrony has been empirically shown to normalize theBrugada syndrome pattern and correct the conduction and activationabnormalities caused by the syndrome. As further described below withreference to FIGS. 5 and 6 the selection of the pacing site can beaccomplished using an apparatus that quantifies the levels of asynchronypresent when pacing through the electrode 23, 25, 193 is applied to aplurality of potential pacing sites and the pacing site that isassociated with the lowest level of cardiac asynchrony is selected asthe position of the electrode 23, 25, 193. Such apparatus can be the onedescribed in the U.S. Pat. No. 9,392,949, issued on Jul. 19, 2016, toOrtega et al, the disclosure of which is incorporated by reference.Briefly, the apparatus obtains, using either surface electrocardiographyor intracardiac electrodes, cardiac signals from two locations of thepatient's heart; extracts signal information; segments QRS complexes ofthe first signal and the second signal based on the extractedinformation; cross-correlates the QRS complexes of the first and secondsignal to produce a correlation signal; and calculates an indexindicative of the level of asynchrony. Other apparatuses forestablishing the level of asynchrony are possible. The asynchronymeasured can be interventricular asynchrony, though other kinds ofasynchrony, such as intraventricular asynchrony are also possible.

The stimulation of either the region near the His bundle 16 or thepara-Hisian region 17 achieves two simultaneous ends. Three pacing modesare available, (a) dedicated DDD pacing (always ON) with a short AVinterval, (b) on-demand according to QRS width (the latter parameter canbe automatically triggered when QRS is wider than 100 msec), and (c)on-demand according to QRS width, manually compared with an averagingtemplate. There is a programmable pacing duration, whose window is alsoprogrammable from three to ten beats. The modes enable the QRS width tobe analyzed and the proper type of pacing provided, as further describedinfra with reference to FIG. 13.

In a further embodiment, as Brugada syndrome is not present at alltimes, but instead appears and disappears as the conditions of thepatient change, the presence of the Brugada syndromeelectrocardiographic pattern can be sensed in an algorithmic way thatenables stimulation delivery only when necessary, after an appropriateAV interval; ventricular stimulation is triggered upon the sensing ofthe atrial depolarization followed by a waiting period that constitutesthe longest practicable interval that avoids bringing back the Brugadasyndrome electrocardiographic pattern.

The twofold aim of detecting the presence of Brugada syndrome andbypassing the syndrome's defects can be provided by delivering cardiacepisode-focused stimuli in the region near the His bundle 16 orpara-Hisian region 17. FIG. 4 is a flow diagram showing a method 60 fortreating Brugada syndrome through triggered pacing in accordance withone embodiment. The method 60 provides an algorithm for initiation ofthe pacing device, informing the physician of incorrect lead position,as appropriate, optimizing the pacing voltage, and deciding on whetherto continue the ventricular stimulation upon the presence of Brugadasyndrome physiology. The method 60 is operable on an implantable CRMdevice 19 under programmatic control, such as program code executable asa series of process or method modules or steps by the device's controlcircuitry, as described supra with reference to FIG. 1.

In a further embodiment, in addition to providing pacing through thepacing electrodes 23 in the region near the His bundle 16 or para-Hisianregion 17, the implantable CRM device 19 can also wirelessly communicatewith an external electrocardiographic system, as further described infrawith reference to FIG. 11, which can sense whether the physiologyindicative of the presence of Brugada syndrome is exhibited in thepatient's electrocardiogram. By collaborating with the externalelectrocardiographic system, energy consumption of the implantable CRMdevice 19 can be minimized by limiting the amount of ventricular pacingdelivered to the patient 10. The external electrocardiographic systemhelps the implantable CRM device 19 to avoid situations of creating apropagation wave front with inferior hemodynamic and functional efficacyin comparison to a normal propagation wave front, for instance, due toless than optimum lead positioning. In a still further embodiment, themethod 60 is operable on a transiently-introduced electrophysiologycatheter 190, in conjunction with an external pulse generator 191, suchas used to induce ventricular arrhythmias during EPS.

Optionally, if the therapeutic electrical stimulation delivered by theCRM device 19 does not include at least two single-phased superimposedwaveforms of opposite polarity with respect to the indifferentelectrode, a site for delivering therapeutic stimulation by the pacingelectrode is selected in the region near the His bundle 16 or thepara-Hisian region 17 (step 61), as further described below withreference to FIG. 15. The selection is typically performed during theimplantation of the CRM 19, though other times to perform the selectionare possible. During the selection, pacing that includes only waveformsof the same polarity is applied through the electrode 23, 25 to aplurality of potential pacing sites, and a level of asynchronyassociated with each of the pacing sites is quantified, such asdescribed above with reference to FIG. 1. Of the sites that areevaluated, the pacing site with the lowest measured asynchrony level isselected as the site where the electrode 23 is positioned for deliveringpacing during treatment.

Once the CRM device 19 is installed, the patient's physiology ismonitored to detect the presence of Brugada syndrome (step 62).Detection can be performed by first sensing cardiac physiology throughthe sensing amplifiers 34 and then providing the physiology to theexternal electrocardiographic system, as further described infra withreference to FIG. 11, which algorithmically identifies physiologyindicative of a presence of Brugada syndrome in the patient 10.Alternatively, the detection can be performed by the sensing amplifiers34 and the control circuitry of the implantable CRM device 19. If thesyndrome is not present (step 62), no further action need be undertakenand, at later points in time, the presence of Brugada syndrome is againrepeatedly detected (step 61).

Upon a finding of the presence of Brugada syndrome in the patient 10(step 63), the patient's physiology is monitored to detect an event,specifically, propagation of an activation wave front proceeding fromthe AV node 36 of the patient's heart, either in region near the Hisbundle 16 or para-Hisian region 17 (step 64), as applicable. Thedetection can be performed by the sensing amplifiers 34 and the controlcircuitry of the implantable CRM device 19. If present (step 65),electrical stimulation therapy is delivered from the pulse generatoroutput circuitry 33 (step 66), which initiates pacing at an AV delaytriggered by atrial event sensing in the region near the His bundle 16or para-Hisian region 17, or 50 msec, whichever is lower, at a pacingamplitude of about 1.2 times threshold. If detection is being performedusing a transiently-introduced electrophysiology catheter, the samecatheter can also be used to stimulate the region. Pacing is timed to bedelivered substantially coincident to the arrival of the atrial event tothe His bundle 16 or para-Hisian region 17. A few microseconds delay canoccur between the arrival of the activation wave front and theinitiation of delivery of electrical stimulation to the region. However,from the standpoint of cardiac myocytes, the delay is de minimus and theelectrical stimulation is received simultaneously as part of theactivation wave front timed to the waveform of the atrial activation.

Pacing continues for a predetermined period of time. The pacing will bemaintained for 80 to 99% of the time, as physician-programmable due toits patient dependence, to enable for windows of time with no pacing, toverify if the pattern remains in the absence of pacing or that thesyndrome has satisfactorily resolved due to a favorable change in thesubstrate of the patient's heart. Pacing is continued for a therapyinterval that the health care personnel adjusts to the actual clinicalsubstrate of the patient being treated. In the rare case of a patient inwhich the Brugada syndrome resolves in a spontaneous manner, the healthcare personnel may program a long interval, whereas a short interval maybe more appropriate for a patient in which Brugada syndromemanifestations tend to appear for only brief periods of time.

During pacing, the patient's physiology is periodically monitored todetect the presence of Brugada syndrome (step 67), in the same mannerdescribed supra, which also confirms that the pacing amplitude of 1.2times threshold is sufficient to suppress the Brugada syndromemanifestations. If the syndrome is still present (step 68), the pacingamplitude is increased (step 71) until a programmable maximum amplitudeof 15 to 30 volts is reached, in which case the physician is advised toreview the position of the lead. Thus, if the maximum allowable pacingamplitude has been reached (step 72), a problem likely exists and achange in ventricular pacing lead position is indicated (step 73), afterwhich pacing stops (step 70) and the method ends.

Otherwise, if the syndrome is not present, yet the predetermined periodof time for pacing has not yet expired (step 69), the patient'sphysiology is again monitored to detect the presence of Brugada syndrome(step 67), as described supra. However, if the predetermined period oftime for pacing has expired (step 69), pacing is stopped (step 70) andthe method ends.

The foregoing method relied on the direct early detection of the arrivalof the activation wave front to the region near the His bundle 16 orpara-Hisian region 17. Alternatively, atrial activity can be sensed inlieu of or in addition to His or para-Hisian events. FIG. 5 is a flowdiagram showing a method 80 for treating Brugada syndrome throughoptimized atrioventricular nodal pacing in accordance with a furtherembodiment. The method 80 provides an algorithm for initiation of thepacing device, informing the physician of incorrect lead position, asappropriate, optimizing AV delay and pacing voltage, and deciding onwhether to continue the ventricular stimulation upon the presence ofBrugada syndrome physiology. The method 80 is operable on an implantableCRM device 19 under programmatic control, in wireless communication withan external electrocardiographic system, or on a transiently-introducedelectrophysiology catheter 190, in conjunction with an external pulsegenerator 191, as described supra.

Parts of the method are the same as performed for the direct earlyactivation wave front detection method. Optionally, if the therapeuticelectrical stimulation delivered by the CRM device 19 does not includeat least two single-phased superimposed waveforms of opposite polaritywith respect to the indifferent electrode, a site for deliveringtherapeutic stimulation by the pacing electrode is selected in theregion near the His bundle 16 or the para-Hisian region 17, as furtherdescribed below with reference to FIG. 15 (step 81). The selection istypically performed during the implantation of the CRM 19, though othertimes to perform the selection are possible. During the selection,pacing that includes only waveforms of the same polarity is appliedthrough the electrode 23, 25 to a plurality of potential pacing sites,and a level of asynchrony associated with each of the pacing sites isquantified, such as described above with reference to FIG. 1. Of thesites that are evaluated, the pacing site with the lowest measuredasynchrony level is selected as the site where the electrode 23 ispositioned for delivering pacing during treatment.

Following the implantation, the patient's physiology is monitored todetect the presence of Brugada syndrome (step 82). Detection can beperformed by first sensing cardiac physiology through the sensingamplifiers 34 and then providing the physiology to the externalelectrocardiographic system, which algorithmically identifies physiologyindicative of a presence of Brugada syndrome in the patient 10.Alternatively, the detection can be performed by the sensing amplifiers34 and the control circuitry of the implantable CRM device 19. If thesyndrome is not present (step 83), no further action need be undertakenand, at later points in time, the presence of Brugada syndrome is againrepeatedly detected (step 82).

Upon a finding of the presence of Brugada syndrome in the patient 10(step 83), the patient's physiology is monitored to detect an atrialactivation event (step 84). The detection can be performed by thesensing amplifiers 34 and the control circuitry of the implantable CRMdevice 19. If an atrial activation event is detected (step 85),electrical stimulation therapy is delivered from the pulse generatoroutput circuitry 33 (step 86), which initiates pacing at an AV delaytriggered by the atrial activity sensing; atrial pacing, where thepatient 10 requires atrial pacing, that is equal to 50% of the previousinterval between atrial and ventricular sensing; or 50 msec, whicheveris lower, at a pacing amplitude of about 1.2 times threshold. Pacingcontinues for a predetermined period of time.

During pacing, the patient's physiology is periodically monitored todetect the presence of Brugada syndrome (step 87), in the same mannerdescribed supra, which also confirms that the pacing amplitude of 1.2times threshold is sufficient to suppress the Brugada syndromemanifestations. If the syndrome is still present (step 88), the pacingamplitude is increased (step 96) until a programmable maximum amplitudeof 15 to 30 volts is reached, in which case the physician is advised toreview the position of the lead. Thus, if the maximum allowable pacingamplitude has been reached (step 97), a problem likely exists and achange in ventricular pacing lead position is indicated (step 98), afterwhich pacing stops (step 95) and the method ends.

Once the lowest voltage at which the manifestations of Brugada syndromeare removed has been found, the atrioventricular AV delay is increased.The delay between atrial activation events is optimized to reflect thelongest AV delay permitted without affecting the reappearance of theBrugada syndrome manifestations. The AV delay is fine-tuned bycontinually monitoring the patient's physiology to detect the presenceof Brugada syndrome. Otherwise, if the syndrome is not present (step88), the AV delay is increased (step 89). The AV delay is slowlyincreased in steps of one to 20 msecs, with 5 msecs being preferable,until the Brugada syndrome electrocardiographic pattern reappears.Following a period of pacing, the patient's physiology is once againmonitored to detect the presence of Brugada syndrome (step 90), in thesame manner described supra. If the syndrome is no longer present (step91) and the maximum AV delay has not yet been reached (step 92), the AVdelay is again increased (step 89). However, if the maximum AV delay hasbeen reached without affecting the reappearance of the Brugada syndromemanifestations (step 92), the AV delay is shorted back to the previousAV delay (step 93) and pacing is continued for a therapy interval thatthe health care personnel adjusts to the actual clinical substrate ofthe patient 10 being treated. Using the longest AV delay that stillremoves the undesired effects of Brugada syndrome ensures that theoptimal preload will be minimally affected by the stimulation, thusmaintaining near normal hemodynamics in the heart. The pacing will bemaintained for 80 to 99% of the time, as physician-programmable due toits patient dependence, to enable for windows of time with no pacing, toverify if the pattern remains in the absence of pacing or that thesyndrome has satisfactorily resolved due to a favorable change in thesubstrate of the patient's heart.

If the predetermined period of time for pacing has expired (step 94),pacing is stopped (step 95) and the method ends.

As battery technology improves and processing power becomes lessexpensive in terms of cost and battery life, the algorithm to detect thepresence of the Brugada syndrome electrocardiographic pattern could beinternally implemented as part of the control circuitry of theimplantable CRM device 19. FIG. 6 is a flow diagram showing a method 100for selecting an algorithm for detecting Brugada syndrome for use inconjunction with the methods of FIGS. 4 and 5. To select an appropriateBrugada syndrome detection algorithm, the patient's physiology wouldfirst be evaluated (step 101), then compared to against a set of storedpredefined algorithms (step 102). A new algorithm specific to thepatient could be created from the physiology (step 105) if desired (step104). Depending upon the cost tradeoffs of development, production,maintenance, regulatory compliance, and other factors at the time ofproduction, an individualized algorithm could be created that maps foreach patient the changes in the intracardiac electrocardiographicpatterns that are detected with the implanted sensing electrodes 24, 26to the presence or absence of the Brugada syndrome electrocardiographicpattern as registered by an external electrocardiographic system.Otherwise, a best matching detection algorithm could be chosen for thepatient 10 (step 105), whether a standard “one size fits all” algorithm,an algorithm selected from a set of generic algorithms to coverdifferent classes of patients, or other suitable form of detectionalgorithm.

Once selected, the detection algorithm can be provided to theimplantable CRM device 19 (step 106), or to an externalelectrocardiographic system, external sensor, or programmer, ifdetection of Brugada syndrome is being performed transiently, such asduring EPS. During use, the device will match the electrographicdifferences detected by the sensing electrodes 24, 26 with the Brugadasyndrome electrocardiographic pattern specified in the detectionalgorithm for the patient 10.

In a still further embodiment, an individualized algorithm could bedeveloped directly from the patient's physiology and automaticallyuploaded into the device used for Brugada syndrome detection. Thisapproach would have the advantage of not limiting the set of parametersthat would need to be adjusted to ensure an univocal match between theBrugada syndrome electrocardiographic pattern, as detected by anexternal ECG system, and by the internal algorithm in the implantableCRM device 19, or external device, as applicable. In addition, advancesin signal processing would enable continual creation of improveddetection algorithms, even after the device has already been implantedin the patient 10. Still other ways to formulate Brugada syndromedetection algorithms and to equip an implantable CRM device 19 orexternal device are possible.

The precise mechanism by which Brugada syndrome causes arrhythmias isunknown, but has been theorized to be due to transmural depolarizationdispersion or transepicardial repolarization dispersion, which can leadto reentrant VTs in Phase 2. Brugada syndrome is characterized byalterations in several ion channels, and, in particular, changes in thesodium ion channel with overexpression of cardiac transient outwardpotassium current. These changes are mainly expressed in the epicardiumwith higher endo-to-epi repolarization gradients that facilitate there-entry mechanisms in polymorphic cells.

The cardiac stimulation delivered by the implantable CRM device 19, orexternal device, as applicable, used in treating Brugada syndromecompensates for electrical shifts in the balance of thevoltage-dependent sodium, potassium and, eventually, calcium ionchannels by applying a relatively intense electrical field. Thiselectrical field facilitates normalizing those channelopathies, afterwhich the electrocardiographic signs of Brugada syndrome disappear,along with the specter of its sudden death manifestation. To enable thefollowing physician or health care provider to verify the disappearanceof the electrocardiographic manifestations of Brugada syndrome, thecardiac stimulation must not be allowed to produce alterations in theelectrocardiogram that could mask the signs typical of Brugada syndrome,for instance, the left ventricular bundle block image of rightventricular apical pacing. The normal conduction through theHis-Purkinje system produces a fast, sequential, synchronousdepolarization of the myocardial fibers, making the ventricularcontraction more efficient. Consequently, the region near the His bundle16 and the para-Hisian region 17 are ideal pacing sites for maintaininga normal activation pattern and enabling the verification of thedisappearance of the Brugada syndrome electrocardiographic pattern.

A foregoing approach allows the generation of an activation wave frontwith near-normal ventricular depolarization and narrow QRS complexes inpatients that already exhibit narrow basal QRS complexes. This type ofactivation wave front is well suited to eliminating the typicalelectrocardiographic signs of Brugada syndrome. Near-physiologicstimulation is delivered substantially simultaneously to atrialactivation by using a “virtual electrode” that allows the creation of astimulation field far stronger than a conventional electrode, which cancorrect the depolarization and conduction abnormalities present inBrugada syndrome. Moreover, this stronger stimulation field entrainsareas that are farther away from the actual pacing site and can therebyovercome conduction disturbances. Thus, the use of this “virtualelectrode” facilitates locating the pacing electrodes 23 in a location,specifically, the region near the His bundle 16 or para-Hisian region17, that allows the health care operator to correct and effectivelyeliminate the Brugada syndrome electrocardiographic pattern, therebyobviating the need to perform complex electrophysiologic mappingprocedures to define the stimulation site.

As delivered through the pacing electrodes 23, the high-energystimulation at septal level modifies the electrocardiographic pattern inleads V1, V2, V3 through a “homogenizer effect” over the transmuralepicardium/endocardium voltage gradient by acting on the involvedvoltage-dependent ionic channels and restoring an adequateepicardium/endocardium voltage ratio. There is also a homogenizingeffect on the epicardium/endocardium repolarization dispersion, as wellas in the intraepicardiac dispersion. The efficacy of the stimulationherein provided is theorized to be based on the fundamentallyvoltage-dependence, and consequently the “virtual electrode effect” atseptum level, of the ionic sodium and potassium cellular channels. Thestimulation could be modifying the altered charges in the epicardiumarea of the right ventricular outflow tract, which is close to thepacing sites used, that is, the region near the His bundle 16 and thepara-Hisian region 17 of the heart 11. Alternatively, the “virtualelectrode effect” may simply be due to the increase in the initialdepolarization voltage, correcting and activating a small number (aboutone percent) of “slow” sodium channels, consequently eliminating theoverexpression of the potassium current (Ito) evident in theelectrocardiogram by elimination of the Brugada syndrome-typical patternin leads V1, V2, V3. Last, a “tsunami effect” that modifies all thecurrents, including those of sodium, potassium and calcium in itsvarious forms, may be triggered through the pacing and thus preventingreentry in Phase 2.

The waveforms and amplitudes used in the electrical stimulationdelivered through the foregoing methods described supra with referenceto FIGS. 4 and 5, by the implantable CRM device 19, or external device,as applicable, have been verified through clinical experiments to bypassthe activation and conduction problems underlying the Brugada syndromeelectrocardiographic pattern. FIGS. 7A-B, 8A-B and 9A-B are graphsrespectively showing, by way of example, 12-lead electrocardiograms forpatients exhibiting Brugada syndrome following treatment through themethods of FIGS. 4 and 5 that involved application of two single-phasedsuperimposed waveforms of opposite polarity with respect to theindifferent electrode. Referring first to FIGS. 7A-B, the patientexhibiting manifestations of Brugada syndrome, as described supra withreference to FIG. 1, has undergone pacing in the para-Hsian region 17.Following therapy, several differences in cardiac profile can be noted,including a change of axis and elimination of left anterior fascicularblock (box 1), a change in pattern in lead augmented vector right (aVR)(box 2), a disappearance of Brugada syndrome pattern in leads V1 and V2(box 3), and a post-pacing reappearance of the syndrome'smanifestations. No changes in J point or T wave in lead V3 areexhibited.

Referring next to FIGS. 8A-B, the patient exhibiting manifestations ofBrugada syndrome, as described supra with reference to FIG. 2, hasundergone pacing in the septal para-Hsian region 17. Following therapy,a change in pattern in aVR and a disappearance of Brugada syndromepattern in leads V1 and V2 can be observed.

Finally, referring to FIGS. 9A-B, the same patient has again undergonepacing in the septal para-Hsian region 17. Following therapy, as before,a change in pattern in aVR (box 1) and a disappearance of Brugadasyndrome pattern in leads V1 and V2 can be observed, as well as apartial reapparition (boxes 2-3) after a few beats and morphology thesame as presented pre-pacing. No changes in J point or T wave in lead V3are exhibited (box 4).

As mentioned above, normalization of the Brugada syndromeelectrocardiographic pattern and the correction of the conduction andactivation abnormalities caused by the Brugada syndrome can be achievedthrough therapeutic electrical stimulation that involves only pacingusing waveforms of the same polarity, conventional pacing waveforms. Theability of the CRM device 19 to achieve this effect through pacing to asite selected based on the level of asynchrony associated with that sitehas been clinically verified. FIGS. 10A-10C are graphs respectivelyshowing, by way of example, 12-lead electrocardiograms (ECG) for apatient exhibiting Brugada syndrome before, during, and afterapplication of therapeutic stimulation involving only conventionalpacing waveforms by the CRM device 19. As can be seen with reference toFIG. 10A, the patient is exhibiting Type 1 Brugada syndrome patternprior to application of therapy, with the ECG of the patient when nostimulation is received being shown between the lines 171, 172. TheBrugada pattern disappeared during application of electrical therapeuticstimulation, as can be seen with reference to FIG. 10B, where the ECG ofthe patient experienced during the application of the stimulation isshown to the right of the line 173. The CRM device 19 used to deliverthe stimulation is an ICD, with the endocardial lead 19 being a screw-indefibrillation lead, with the pacing electrode 23 being placed in thePara-Hisian region. Following the termination of the para-Hisianstimulation, the Brugada pattern reappears, as can be seen withreference to FIG. 10C, where the ECG of the patient following cessationof the stimulation is shown between the lines 174, 175.

Similar results are shown with respect to FIGS. 11A-11C, which show byway of example, 12-lead electrocardiograms for a second patientexhibiting Brugada syndrome before, during, and after application oftherapeutic stimulation involving only waveforms of the same polarity bythe CRM device 19. As can be seen with reference to FIG. 11A, thepatient exhibits Type 1 Brugada pattern prior to beginning of thestimulation, with the ECG of the patient when no stimulation is receivedbeing shown between the lines 176, 177. The application of thestimulation in the same manner as described above with reference to FIG.10B causes the disappearance of the Brugada pattern, as seen withreference to FIG. 11B. The pattern reappears following the cessation ofstimulation, as can be seen with reference to FIG. 11C, where the ECG ofthe patient following cessation of the stimulation is shown to the leftof the line 178.

Likewise, FIGS. 12A-12C, which show by way of example, 12-leadelectrocardiograms for a third patient exhibiting Brugada syndromebefore and during application of therapeutic stimulation by the CRMdevice 19. As can be seen with reference to FIG. 12A, the patientexhibits Type 1 Brugada pattern prior to beginning of the stimulation Ascan be seen with reference to FIGS. 12B-C, the pattern disappears uponapplication of stimulation in the same manner as described above withreference to FIG. 10B, and reappears following cessation of stimulation,as can be seen with reference to FIG. 12C, where the ECG of the patientfollowing cessation of the stimulation being shown between the lines179, 180.

Further, the normalization of the Brugada syndrome achieved throughpacing to a site selected based on associated cardiac electricalasynchrony has been empirically shown to be accompanied by a reductionin the patient's cardiac electrical asynchrony. FIG. 17 shows surfaceECG curves representing both right ventricle 161 and left ventricle 162of the same patient whose 12-lead ECG is shown with reference to FIG.10A and which are contemporaneous to the 12-lead ECG shown in FIG. 10A.Both positive curves 161, 162 with QRS final portion delay withoutcomplete overlapping of two curves. An asynchrony area is evidenced. Theasynchrony is reduced once the stimulation is applied, as can be seenwith reference to FIG. 18. FIG. 18 shows surface ECG curves representingboth right ventricle 161 and left ventricle 162 of the same patientwhose 12-lead ECG is shown with reference to FIG. 10B and which arecontemporaneous to the 12-lead ECG shown in FIG. 10B. As can be seenwith reference to FIG. 18, during the application of the septalstimulation in the para-Hisian region, QRS final portion delaydisappeared and a completely synchronous QRS is shown with two fullyoverlapping curves.

The three pacing modes enable the QRS width to be analyzed and theproper type of pacing provided. FIG. 13 is a flow diagram showing amethod 100 for sensing QRS width for use in conjunction with the methodsof FIGS. 4 and 5. The implantable CRM device 19 has at least threeprogrammable parameters for pacing, which are para-Hisian, apex, or bothpara-Hisian and apex, and at least two values that reflect changes inthe QRS width, which are coil-to-coil and ring-to-distal coil(programmable).

First, if Brugada syndrome QRS width sensing is not enabled (step 101),sensing and pacing are provided as for a DDD CRT device (step 102).Otherwise, if Brugada syndrome QRS width sensing is enabled (step 101)and the device is set to automatic mode (step 104), the QRS width ismeasured (step 104). If the QRS width is less than 100 msec (step 105),pacing for a short AV interval is provided (step 107). Otherwise, if theQRS width is equal to or greater than 100 msec (step 105), the QRSduration is sensed (step 106). If the device is not set to automaticmode (step 104), a manual adjustment template is used (step 108). If aBrugada syndrome pattern is apparent (step 109), pacing for a short AVinterval is provided (step 107). Otherwise, if a Brugada syndromepattern is not apparent (step 109), the QRS width is sensed (step 110).

The pacing therapy can be delivered wholly in situ via an implantableCRM device 19 that performs sensing, detection algorithm analysis andpacing. Alternatively, the implantable CRM device 19 could be remotelycoupled to an external electrocardiographic system that wouldcollaboratively perform select aspects of the end-to-end treatmentregime. FIG. 14 is a functional block diagram showing acomputer-implemented system 130 for treating Brugada syndrome, inaccordance with a further embodiment. The system 130 includes anexternal electrocardiograph machine 133, conventional externalprogrammer 131 and an external computer 136. Other components are alsopossible.

The external electrocardiograph machine 133, or similar device, cancapture an electrocardiogram of the patient 10 at different points ofthe pacing therapy, as described supra, which can be used to identifyphysiology indicative of a presence of Brugada syndrome in the patient.The external electrocardiograph machine 133 can be a conventionalelectrocardiograph machine that uses a set of twelve precordial leads134 (shown as a single across-the-chest “strap” for the sake ofsimplicity) to record an electrocardiogram. Further, the externalelectrograph machine 133 can be used to determine the level of cardiacelectrical asynchrony that occurs when the therapeutic electricalstimulation is applied via the pacing electrode 23 to the potentialpacing sites. As described in the U.S. Pat. No. 9,392,949, issued onJul. 19, 2016, to Ortega et al, the disclosure of which is incorporatedby reference, at least two of the precordial leads can be used tocollect the signals used to quantify the asynchrony. In a furtherembodiment, the external electrocardiograph machine 133 relies on theimplantable CRM device 19 to temporally capture cardiac cyclephysiology, which is then interpreted by either the externalelectrocardiograph machine 133 or an external computer 136, as describedinfra, into an electrocardiogram or similar form of temporal mapping ofthe cardiac cycle physiology. Likewise, the signals used to evaluate thecardiac electrical asynchrony of the potential pacing sites can beobtained using the sensing electrodes 24, 26 of the CRM device 19. Thesignals, obtained using the external electrograph machine 133 or the CRMdevice, can be processed by the external electrograph machine 133, theexternal computer 136, or another processing device to quantify theasynchrony level associated with application of pacing to each of thepotential pacing sites tested.

The conventional external programmer 131, or similar device, canremotely communicate with the implantable CRM device 19 using aninductive (or wireless) communications channel to enable remoteparametric programming of and stored physiologic data offload from thedevice. The programmer 131 includes a physically-connected programmerwand 132, which is placed by health care personnel over the patient'spectoral region above the implantable CRM device 19 to initiate andcarry out programmer-to-CRM device communications.

The external computer 136, or similar device, can be wirelessly (orinductively) interfaced to the implantable CRM device 12. The externalcomputer 136 receives cardiac cycle physiology, as recorded by theimplantable CRM device 12 via the wireless communications channel.Alternatively, cardiac cycle physiology or, equivalently,electrocardiograms, can be retrieved by the external computer 136 fromthe external electrocardiograph machine 133, or other source. Theexternal computer 136 algorithmically identifies physiology indicativeof a presence of Brugada syndrome in the patient 10. In addition, theexternal computer 136 can create an individualized algorithm for eachpatient 10 that maps the changes in the intracardiacelectrocardiographic patterns that are detected with the implantedsensing electrodes 24, 26 to the presence or absence of the Brugadasyndrome electrocardiographic pattern as registered in the cardiac cyclephysiology or electrocardiograms.

Finally, the system 130 can include a centralized server 137 coupled toa database 138 within which patient data, such as the electrocardiogramsand algorithms, are stored. The external electrocardiograph machine 133,external programmer 131, and the external computer 136 can interfacewith the centralized server 137 through a network 135, such as apublicly available wide area network, including the Internet. Otherforms of remote server interfacing are possible.

In a yet further embodiment, the system 130 can be adapted for use inEPS, whereby a transiently-introduced electrophysiology catheter 190,shown with reference to FIG. 20, serves the functions of the implantableCRM device 19, which can either be temporarily rendered inoperable or beabsent from the patient 10 altogether.

Identifying pacing sites associated with a minimal level of cardiacasynchrony allows to treat Brugada syndrome with conventional waveformpacing. FIG. 15 is a flow diagram showing a routine 150 for selecting asite for delivering therapeutic stimulation by the pacing electrode inthe region near the His bundle 16 or the para-Hisian region 17 for usein the methods of FIGS. 4 and 5 in accordance with one embodiment. Whilein the description below, the endocardial lead 21 is described as ascrew-in lead, in a further embodiment, use of other kinds of leads 21is possible. Initially, the endocardial screw-in lead 21 is insertedinto the patient 10 (step 151). Right or left venous access can be usedfor the insertion. Cephalic, subclavian or axillary venous approach canbe used through dissection or puncture for the insertion. If puncture isused, a peel-away sheath is placed over a short guidewire. Theendocardial lead 21 is then advanced towards the peel-away sheath guidedby fluoroscopy. The lead 21 is positioned in pulmonary artery. A curvedstylet is advanced into the lead 21. Then the stylet is located andfixed in atrial floor. The lead 21 is removed slowly while the styletremains fixed. At this time, right ventricular septal zone is mappedwith an apparatus that determines a level of cardiac asynchronyassociated with each of the pacing sites in the zone (step 152), such asthe apparatus described in the U.S. Pat. No. 9,392,949, issued on Jul.19, 2016, to Ortega et al, the disclosure of which is incorporated byreference. One of the septal sites is selected for further pacing basedon the mapping (step 153), with the pacing site associated with a lowestlevel of asynchrony. In one embodiment, the site most closely associatedwith an asynchrony curve shown with reference to FIG. 16 is selected.FIG. 16 shows surface ECG curves representing both right ventricle 161and left ventricle 162 of a patient superimposed in their final portion,with the left ventricle and the right ventricle exhibiting a high degreeof synchrony. In a further embodiment, other expressions of asynchrony,such as asynchrony indices, can be used to select the pacing site.

Returning to FIG. 15, once the pacing site is selected, the screw of thelead 21 is released and the stylet is removed, (step 154). Sensing andthreshold measurements are performed (step 155). Defibrillationthreshold is tested to ensure that defibrillation that can be deliveredis capable of terminating arrhythmia (156). If the sensing and thresholdmeasurements and the tested defibrillation threshold in steps 155 and156 are within normal ranges (step 157), the lead 21 is then fixed inthe selected site as the final position (158), allowing pacing describedabove beginning with reference to steps 62 and 82 and ending the routine150. If the sensing and threshold measurements and the testeddefibrillation threshold in steps 155 and 156 are not within a normalrange (step 157), a different site is selected based on the asynchronydata obtained in step 153, the lead 21 is repositioned in a thedifferent site (step 160), and the routine 150 returns to step 155.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope.

What is claimed is:
 1. A system for treating Brugada syndrome,comprising: a cardiac pacing device comprising a pulse generator and atleast one pacing electrode that is electrically coupled to the pulsegenerator via an endocardial lead, the at least one pacing electrodeconfigured to be positioned in one of a plurality of potential pacingsites that is selected based on a level of cardiac electrical asynchronyassociated with that potential pacing site, the selected potentialpacing site located in one of a region near the His bundle and apara-Hisian region of a patient's heart, the pulse generator configuredto deliver through the at least one pacing electrode therapeuticelectrical stimulation substantially coincidentally to propagation of anactivation wave front proceeding from the atrioventricular node of thepatient's heart when the at least one pacing electrode is positioned atthe selected potential pacing site.
 2. A system according to claim 1,wherein the endocardial lead is a screw-in lead.
 3. A system accordingto claim 1, wherein the cardiac pacing device is an implantablecardioverter-defibrillator and the endocardial lead is a defibrillationlead.
 4. A system according to claim 1, further comprising: a processingdevice configured to determine the level of cardiac electricalasynchrony associated with the selected potential pacing site when thetherapeutic electrical stimulation is applied to that site and todetermine levels of cardiac electrical asynchrony associated with theremaining potential pacing sites when the therapeutic electricalstimulation is applied to the remaining potential pacing sites, whereinthe level of cardiac electrical asynchrony associated with the selectedpotential pacing site is less than the levels of cardiac electricalasynchrony associated with the remaining potential pacing sites.
 5. Asystem according to claim 1, wherein all of waveforms comprised withinthe therapeutic electrical stimulation are of a same polarity.
 6. Asystem according to claim 1, further comprising: a sensing amplifieroperatively coupled to the pulse generator and configured to sense viaat least one sensing electrode an atrial event comprising the activationwave front proceeding from the atrioventricular node to the region nearthe His bundle or the para-Hisian region, the diagnostic module furtherconfigured to control the pulse generator in delivering the therapeuticelectrical stimulation in response to the atrial event.
 7. A systemaccording to claim 1, further comprising: a delay module operativelycoupled to the pulse generator and configured to determine a waitingperiod comprising a time interval between successive deliveries of thetherapeutic electrical stimulation that avoids reoccurrence of theBrugada syndrome electrocardiographic pattern, wherein the pulsegenerator is further configured to wait out the waiting period beforedelivering the therapeutic electrical stimulation.
 8. A system accordingto claim 1, further comprising: a voltage module operatively coupled tothe pulse generator and configured to determine a lowest voltage atwhich manifestations of Brugada syndrome are removed, wherein the pulsegenerator is further configured to deliver the therapeutic electricalstimulation at the lowest voltage.
 9. A system according to claim 1,further comprising: a diagnostic module operatively coupled to the pulsegenerator and configured to sense via at least one sensing electrodephysiology indicative of a presence of Brugada syndrome in the patient,the diagnostic module further configured to control the pulse generatorin delivering the therapeutic electrical stimulation in response to thepresence of Brugada syndrome.
 10. A system according to claim 9, furthercomprising: a memory store comprised in the diagnostic module andconfigured to store a plurality of profiles for use by the diagnosticmodule against which to compare the physiology indicative of a presenceof Brugada syndrome in the patient, wherein one of the profiles is bythe diagnostic module selected prior to sensing the physiology.
 11. Asystem according to claim 9, further comprising: an analysis moduleoperatively coupled to the diagnostic module and configured to evaluatethe physiology indicative of a presence of Brugada syndrome asdetermined to be specific to the patient and to define parameters forthe at least two single-phased superimposed waveforms; and thediagnostic module further configured to control the pulse generator indelivering the at least two single-phased superimposed waveforms per theparameters in response to the presence of Brugada syndrome.
 12. A systemfor catheter-based treatment Brugada syndrome, comprising: anelectrophysiology catheter configured to be transiently introduced intoa patient's heart; and a pulse generator and at least one pacingelectrode that is electrically coupled to the pulse generator via thedefibrillation lead, the at least one pacing electrode configured to bepositioned in one of a plurality of potential pacing sites that isselected based on a level of cardiac electrical asynchrony associatedwith that potential pacing site, the selected potential pacing sitelocated in one of a region near the His bundle and a para-Hisian regionof a patient's heart, the pulse generator configured to deliver throughthe at least one pacing electrode therapeutic electrical stimulationsubstantially coincidentally to propagation of an activation wave frontproceeding from the atrioventricular node of the patient's heart whenthe at least one pacing electrode is positioned at the selectedpotential pacing site.
 13. A system according to claim 12, wherein allof waveforms comprised within the therapeutic electrical stimulation areof a same polarity.
 14. A system according to claim 12, furthercomprising: a sensing amplifier operatively coupled to the pulsegenerator and configured to sense via at least one sensing electrode anatrial event comprising the activation wave front proceeding from theatrioventricular node to the region near the His bundle or thepara-Hisian region, the diagnostic module further configured to controlthe pulse generator in delivering the therapeutic electrical stimulationin response to the atrial event.
 15. A system according to claim 12,further comprising: a delay module operatively coupled to the pulsegenerator and configured to determine a waiting period comprising a timeinterval between successive deliveries of the therapeutic electricalstimulation that avoids reoccurrence of the Brugada syndromeelectrocardiographic pattern, wherein the pulse generator is furtherconfigured to wait out the waiting period before delivering thetherapeutic electrical stimulation.
 16. A system according to claim 12,further comprising: a voltage module operatively coupled to the pulsegenerator and configured to determine a lowest voltage at whichmanifestations of Brugada syndrome are removed, wherein the pulsegenerator is further configured to deliver the therapeutic electricalstimulation at the lowest voltage.
 17. A system according to claim 12,further comprising: a processing device configured to determine thelevel of cardiac electrical asynchrony associated with the selectedpotential pacing site when the therapeutic electrical stimulation isapplied to that site and to determine levels of cardiac electricalasynchrony associated with the remaining potential pacing sites when thetherapeutic electrical stimulation is applied to the remaining potentialpacing sites, wherein the level of cardiac electrical asynchronyassociated with the selected potential pacing site is less than thelevels of cardiac electrical asynchrony associated with the remainingpotential pacing sites.
 18. A system for treating Brugada syndrome usingcardiac electrical asynchrony data, comprising: a processing deviceconfigured to determine, for a plurality of potential pacing sites in atleast one of a region near the His bundle and a para-Hisian region of apatient's heart, a level of cardiac electrical asynchrony associatedwith an application of therapeutic electrical stimulation to each of theplurality pacing sites; and a pulse generator electrically coupled toone of an endocardial lead and a physiological catheter and configuredto deliver electrical therapeutic stimulation under programmedparametric control through an at least one pacing electrode, the atleast one pacing electrode comprised on one of the endocardial lead andthe physiological catheter, substantially coincidentally to propagationof an activation wave front proceeding from the atrioventricular node ofthe patient's heart when the at least one pacing electrode is positionedat the potential pacing site associated with the lowest one of thelevels of the cardiac electrical asynchrony.
 19. A system according toclaim 18, wherein the cardiac pacing device is an implantablecardioverter-defibrillator and the endocardial lead is a defibrillationlead.
 20. A system according to claim 18, further comprising: adiagnostic module operatively coupled to the pulse generator andconfigured to sense via at least one sensing electrode physiologyindicative of a presence of Brugada syndrome in the patient, thediagnostic module further configured to control the pulse generator indelivering the therapeutic electrical stimulation in response to thepresence of Brugada syndrome.